Hyponatremia is the most common electrolyte abnormality seen in a general hospital population. Hyponatremic brain damage appears to represent a major but poorly recognized public health problem, with a projected morbidity in the United States of more than 5,000 per year. Age and gender are major factors predisposing to brain damage from hyponatremia. Plasma vasopressin levels are increased in virtually all hyponatremic patients and vasopressin has a number of deleterious effects upon brain homeostasis. The major questions to be addressed in this proposal relate to the effects of sex steroid hormones and neuropeptides on the susceptibility of the brain to injury from hyponatremia. Hyponatremic brain damage appears to involve an interaction between vasopressin (AVP) and gonadal steroid hormones, resulting in impaired cerebral microcirculation and cytotoxic brain edema. The integrity of the cerebral microcirculation will be quantitatively evaluated in hyponatremic rats, using perfusion sensitive MRI in vivo. Cytotoxic brain edema will be evaluated on the basis of changes in the distribution of cell water between intra- and extra-cellular compartments. Changes in this distribution will be evaluated by means of the apparent diffusion coefficient (ADC), which is determined using diffusion-weighted MRI. In addition to the osmotic effects of hyponatremia, it appears that sex steroid hormones affect brain adaptation at the level of volume regulatory mechanisms in neuronal and glial cell membranes, in particularly by impairing in ion transport through the Na+ -K+ ATPase system, the Na+/Ca2+ exchanger, and the Na+/H+ exchanger. These important pathways for brain cell volume regulation will be evaluated in vitro in synaptosomes from the brains of normonatremic and hyponatremic rats, untreated or pretreated with steroid hormones. The effect of sex steroid hormones on volume regulation in brain astrocytes and the most important pathway for regulation of cell volume in response to hyponatremia, the Na+ -K+ ATPase system, will be evaluated in vitro in astrocytes in culture. The sex steroid hormones will be administered in vivo to those groups of rats in which synaptosome studies will be carried out, while they will be administered in vitro (in the astrocyte culture medium) to the astrocytes in culture. Our clinical and experimental studies suggest that the pathogenesis of hyponatremic encephalopathy involves multiple interactive mechanisms and that permanent brain damage from hyponatremia results from a failure of brain adaptation, which is most severe in cyclic (menstruant) females and prepubertal individuals. In this proposal we will determine the pathophysiology of hyponatremic brain damage by determining the role of the interactive components, particularly endogenous neuropeptides and steroid hormones, impaired pathways for extrusion of sodium and potassium, reduction of cerebral perfusion, and redistribution of cell water between intra- and extra-cellular components.